Based on linkage analysis in Pima Indians, we have located a genetic element at 1p31 the first phase of insulin secretion in response to an intravenous glucose infusion. We have genotyped additional markers in the regions of linkage on chromosome 1, and have completed a YAC contig and physical map this region covering approximately 9 cM to further refine and localize this genetic element that influences this aspect of insulin secretion. The map spans approximately 9 megabases of DNA includes loci encoding phosphoglucomutase 1 (PGM1), janus kinase 1 (JAK1), phosphodiesterase 4B (PDE4B), c-JUN (JUN), GADD45 (GADD45) and the leptin receptor (LEPR). The structure of the leptin receptor, a candidate gene, was reduced and all 20 exons sequenced in 20 individuals. Sequence analysis uncovered several nucleotide substitutions that result in amino acid substitutions. Two common polymorphisms in the leptin receptor gene (LEPR) were genotyped in 1300 Pima Indians. The amino acid substitutions at amino acid 223 are associated with changes in circulating leptin levels and with NIDDM. Aldose reductase was sequenced in individuals with end stage renal disease. No amino acid substitutions found and the promoter is intact. HNF-4a was sequenced in young onset diabetics and a single amino acid substitution was found. This substitution was not associated with NIDDM.